Diabetes mellitus is a major health problem in the United States affecting approximately 13 million people. The five "classic" complications which have historically been associated with the condition are microangiopathy, neuropathy, nephropathy, macrovascular disease, and delayed wound healing. Recently, however, periodontal disease (PD) has been declared the "sixth" major complication of diabetes as diabetics demonstrate an increased incidence/severity of PD. The cellular/molecular basis for diabetic PD is unknown. Our preliminary data suggest that PD and delayed dermal wound haling are manifestations of the same general systemic deficit in diabetes. This deficit involves impairment of the cellular/molecular signal of wounding via reduced macrophage growth factor/cytokine production. We have assembled a team of investigators representing the basic sciences, clinical medicine, and dentistry to address this important issue. The major hypotheses to be tested are; 1) diabetes-induced hyperlipidemia/dyslipidemia interferes with the normal cellular/molecular signal of wounding by alteration of macrophage function; and 2) this diabetes-induced impairment of the wound signal is reversible with control of serum lipids (normalization of low density lipoproteins and triglycerides). Clinical, animal model/in vitro systems, and cellular/molecular analyses will be used to define the wound signal and determine its relationship to delayed dermal would healing and PD. PD will be investigated in the context of a generalized systemic wound healing deficit that manifests as PD in the face of constant pathologic wounding of the gingiva (bacterial plaque) or delayed dermal wound healing in instances of periodic traumatic wounding to other parts of the body. The macrophage will be targeted as the major cell type responsible for amplification/transduction of the wound signal because of its importance in the early phases of wound healing (inflammatory, granulation) and its ability to influence the wound environment via release of many important growth factors/cytokines. Macrophage function will be assessed utilizing immunocytochemical techniques to demonstrate the presence of surface marker antigens/receptors, as well as quantitative competitive reverse transcriptase polymerase chain reaction, in situ hybridization, and radioimmunoassay methodologies to quantitate expression and release of important growth factors/cytokines. It is anticipated that these cellular/molecular studies will provide information concerning defective tissue repair in diabetics that will have clinical relevance for the understanding of PD and delayed wound healing as well as applications of appropriate/specific therapies.